Drug Interaction Report

GENERALLY AVOID: Coadministration with drugs that cause moderate inhibition of CYP450 2C9 and moderate or strong inhibition of CYP450 3A4 may increase the plasma concentrations of siponimod, which is primarily metabolized by these isoenzymes. This interaction includes concomitant use of siponimod with a moderate CYP450 2C9/3A4 dual inhibitor or a moderate CYP450 2C9 inhibitor in combination with a separate moderate or strong CYP450 3A4 inhibitor. In healthy CYP450 2C9*1/*1 genotype volunteers, coadministration of a moderate CYP450 2C9/3A4 dual inhibitor (fluconazole 200 mg daily at steady-state) and siponimod (a single 4 mg dose) resulted in 2-fold and 50% increases in siponimod AUC and terminal half-life, respectively. According to in silico (computer-based) evaluation, use of fluconazole resulted in a 2- to 4-fold increase in the steady-state AUC of siponimod across different CYP450 2C9 genotypes. The CYP450 2C9 genotype influences the fractional contributions of CYP450 2C9 and 3A4 to overall elimination. If the metabolic activity of CYP450 2C9 is decreased, a larger contribution of CYP450 3A4 can be anticipated.

MANAGEMENT: Concomitant use of siponimod with a moderate or strong CYP450 2C9/3A4 dual inhibitor (e.g., fluconazole, mifepristone) or a moderate CYP450 2C9 inhibitor (e.g., abiraterone, amiodarone, fenofibrate, gemfibrozil, nitisinone, oxandrolone) in combination with a moderate or strong CYP450 3A4 inhibitor (e.g., amprenavir, aprepitant, atazanavir, boceprevir, ceritinib, chloramphenicol, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, dalfopristin-quinupristin, darunavir, delavirdine, diltiazem, dronedarone, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosaprepitant, fosnetupitant, fusidic acid, idelalisib, imatinib, indinavir, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, nelfinavir, netupitant, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, troleandomycin, verapamil, voriconazole, voxelotor) is not recommended. Caution is advised if siponimod is used in combination with moderate CYP450 2C9 inhibitors.

ADJUST DOSING INTERVAL: Food may reduce the systemic bioavailability of amprenavir from fosamprenavir oral suspension. The mechanism of interaction has not been described. According to the product labeling, administration of fosamprenavir oral suspension (1400 mg single dose) with a high-fat meal (967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate) reduced amprenavir peak plasma concentration (Cmax) by 46% and systemic exposure (AUC) by 28% compared to administration in a fasted state. The time to reach peak plasma level (Tmax) was delayed by 0.72 hours. In contrast, the same high-fat meal did not affect the pharmacokinetics of amprenavir from fosamprenavir tablets.

MANAGEMENT: Fosamprenavir suspension should be administered on an empty stomach in adults, but with food in pediatric patients to aid palatability and compliance. If emesis occurs within 30 minutes after dosing the suspension, the dose should be repeated. Fosamprenavir tablets may be taken with or without food.